Longitudinal analysis of aflatoxin and gallbladder cancer

Abstract

Background: Aflatoxin has recently been found to be associated with gallbladder cancer in retrospective case-control studies from both Chile and China. We sought to verify this association prospectively using blood samples collected many years before cancer diagnosis of the Shanghai Cohort Study. Methods: The Shanghai Cohort Study enrolled 18,244 men aged 45–64 years in Shanghai, China, during 1986-1989. We identified gallbladder cancer through a population-based cancer registry and annual in-person interview from baseline blood collection until 2017. For each case, we randomly selected two controls from cohort participants who were cancer free at the time of the corresponding case’s cancer diagnosis and were matched to the index case on age (±2 years) and month and year of blood collection. Serum aflatoxin B1-lysine adducts were quantified using isotope dilution mass spectrometry; 84 cases and 168 matched controls had sufficient serum. We estimated age-adjusted odds ratios (ORs) and 95% CIs for the association of gallbladder cancer with aflatoxin B1-lysine adducts above versus below the limit of detection (≥0.5pg aflatoxin-lysine/mg albumin). Results: The median time from blood collection to diagnosis of gallbladder cancer was 18.4 years (range: 1.1-28.1 years). Aflatoxin B1-lysine adducts were detected in 50% of the gallbladder cancer cases (42/84) and 39% of controls (66/168). Detectable aflatoxin B1-lysine adducts were associated with a nearly 2-fold increased risk of developing gallbladder cancer (OR: 1.9, 95% CI: 0.99–3.6). Stratifying by time of diagnosis/matching, the OR for GBC diagnosed less than 15 years after blood draw was 3.33 (95% CI: 0.86–12.88), as compared to 1.56 (0.73–3.31) for GBC diagnosed 15 years or more after blood draw. Conclusion: Aflatoxin B1 is associated with increased risk of developing gallbladder cancer. Aflatoxin levels have been dropping in China due to concerted aflatoxin-abatement efforts. The stronger effect for cancers diagnosed <15 year from blood draw may reflect lower exposure or lack of exposure in the out years, suggesting that continued high-level exposure is needed drive carcinogenesis. Alternatively, it could suggest that aflatoxin has an impact relatively late in the gallbladder carcinogenesis process. In either case, aflatoxin-abatement efforts may help reduce the public health burden of GBC in high-risk areas with aflatoxin exposure.